Process for preparing β-amino-α-benzylacrylonitriles

ABSTRACT

Compounds comprising selected N-substituted β-amino-α-benzyl-acrylonitriles and methods of preparing said compounds substantially free from the corresponding benzalacrylonitrile. 
     The compounds are useful as intermediates in the preparation of antibacterial and antimalarial agents.

This is a continuation of application Ser. No. 263,174, filed on June15, 1972, now abandoned, which is a division of Ser. No. 16,606 filedMar. 4, 1970, now U.S. Pat. No. 3,697,512.

This invention relates to improved methods of preparing5-benzylpyrimidines and more particularly is related to a class ofstable α-benzylacrylonitrile intermediates, and to methods of makingsuch compounds.

2,4,-Diamino-5-benzylpyrimidines possess both antimalarial andantibacterial activities (J. Am. Chem. Soc., 1951, 73, 3758). Maximalantibacterial activity is found among derivatives which bear electrondonating substituents in the benzene nucleus and are unsubstituted inthe 6th position of the pyrimidine moiety.2,4-Diamino-5-(3',4',5'-trimethoxybenzyl) pyrimidine or trimethoprim(U.S. Pat. No. 2,909,522) has a moderately broad antibacterial spectrumwhich includes many of the Gram-positive species but it is also activeagainst species of the genus Proteus. In common with other2,4-diaminopyrimidines it is a competitor of folic and folinic acids inmicroorganisms which require these nutrilites, and it can be shown toinhibit dihydrofolate reductase in Streptococcus faecalis. A strongpotentiative effect is observed when the drug is administered incombination with sulphonamides as a consequence of the sequentialblockade of the biochemical pathway which leads to the de novo synthesisof coenzymes F. This potentiation may be demonstrated both in vitro andin experimental infections in mice with Staphyloccoccus and Proteusspecies.

2,4-Diamino-5-benzylpyrimidines, which includes trimethoprim and2,4-diamino-5-(3',4'-dimethoxybenzyl)pyrimidine or diaveridine and2,4-diamino-5-(3',4'-dimethoxy-5-bromobenzyl)pyrimidine (U.S. Pat. No.2,658,897), may be administered orally at a dose of 1 mg/kg to 30 mg/kgper day.

Preferably these compounds are administered in tablet form to a mammalbeing treated, and trimethoprim may advantageously be combined withsulphamethoxazole against certain respiratory infections. A furtherexample of this class is2,4-diamino-5-(2'-methyl-4',5'-dimethoxybenzyl)pyrimidine (ormetoprim),which has been reported to show antibacterial acitivity, and also hascoccidiostatic properties when combined with sulphadimethoxine.

A new route was developed some years ago for the preparation of2,4-diamino-5-benzylpyrimidines (see Stenbuck, Baltzly and Hood, J. Org.Chem., 1963, 28, 1983 and British Patent Specification No. 957,797).This route comprises the steps of (i) condensing an aromatic aldehydewith a β-substituted propionitrile in the presence of both an alcohol assolvent and a strong base to give a mixture of isomers of formulae (Ia)and (Ib) respectively: ##STR1## wherein Ar is an optionally substitutedphenyl group, Y is an alkoxy, thioalkyl or dialkylamino group, and Z isthe group Y or is an alkoxy group derived from the solvent alcohol; and(ii) reacting either the pure `benzal` isomer (Ia) or a mixture of`benzal` and `benzyl` isomers (Ia) and (Ib) respectively with guanidineto give a 5-benzylpyrimidine of formula ##STR2##

Although it was known that the intermediate product obtained in thefirst step was a mixture of isomers of formulae (Ia) and (b), only the(Ia) `benzal` isomer could be isolated in a crystalline form after somepurification steps. The two isomers were assumed to be in equilibriumwith each other when prepared under alkaline conditions and furtherreacted with guanidine according to the aforesaid disclosures, but itwas not clearly established which of the isomers was primarilyinteracting in the second step. In many cases this mehtod affordsacceptable yields but in certain instances extensive losses (up to abouthalf the material used) ensue from formation of yellow polymers.

The further conversion of composite mixtures of derivatives and isomersaccording to British Patent Specification No. 957,797, afforded therequired 2,4-diamino-5-benzylpyrimidines only is yields between 25 and45%, and in view of the importance of the final products and thedifficulties with by-products and impurities, alternative methods werealso explored by various investigators. For instance, the specificationof South African Patent Application No. 65/5794 discloses a processcomprising the steps of (a) reacting acetylthymine withN-bromosuccinimide to form a acetylbromothymine, (b) condensing theproduct with a substituted benzene, (c) reacting the product with ahalogenating agent, and (d) aminating the halogeno derivative. However,this process suffers from the disadvantages that acetylbromothymine isexpensive to make, condensation with the benzene compound does notprovide the further intermediate in a high yield, and the last stagerequires operation under pressure and usually results in an equilibriumstate with consequent poor yields. Altogether the process requires fourstages to obtain the final product, and none of the stages isparticularly advantageous.

Subsequent developments showed that the polymer formation obtained whenoperating the process described in the specification of British Pat. No.957,797, could be prevented or reduced in cases of β-alkoxy-derivativesof compounds (Ia) and (Ib) by temporarily saturating the double bondwith excess alkoxide in alcohol.

This provides the corresponding acetal of formula (II), for instance,according to the reaction outlined below: ##STR3## When the acetal (II)is subsequently treated with guanidine in alcoholic solution, thealkaline condition is thought to catalyse the reconsititution of thedouble bond, initially in the form of (I'b), and the intermediate canthus react with guanidine to give the desired 5-benzylpyrimidine.

Acetals of formula (II) may also be prepared by condensing thecorresponding aromatic aldehyde with a 3,3-dialkoxypropionitrile andreducing, preferably catalytically, the3,3-dialkoxy-2-benzalpropionitrile intermediate so obtained. (See U.S.Pat. No. 3,487,083).

The aforesaid British Patent Specification No. 957,797 also describes(Example 14) the reaction of veratraldehyde withβ-dimethylaminopropionitrile in the presence of sodium in ethanol togive a mixture of β-dimethylaminoveratralnitrile (III) andβ-ethoxyveratralnitrile (IV) in a 32% yield. ##STR4## It is stated inthe Example that this mixture was subsequently cyclised with guanidineto give 2,4-diamino-5-(3',4'-dimethoxybenzyl)-pyrimidine. It is to benoted that both the compounds (III) and (IV) above are `benzal`derivatives.

It has now been found that N-substituted β-amino-α-benzylacrylonitrilesof the configuration of formula (V) ##STR5## can be prepared remarkablyreadily under a conveniently wide variety of conditions and that theproducts so obtained are not only substantially free of contaminationwith the corresponding `benzal` isomer but manifest an unexpectedstability and capability of maintaining their configuration.

The `benzyl` configuration of these compounds shows little or notendency to isomerise into the `benzal` form prepared and exemplified inthe British Patent Specification No. 957,797. Furthermore, theβ-amino-αbenzylacrylonitriles can be converted into benzylpyrimidines orinto other benzyl derivatives, which may be used as preferred for thepreparation of benzylpyrimidines or other heterocyclic ring systems.

According to the present invention in one aspect therefore there isprovided an N-substituted-β-amino-α-benzylacrylonitrile compound of theformula (V), in a form substantially free from contamination with theβ-amino-α-benzylidenepropionitrile isomer. In particular thecontamination with the `benzal` isomer is normally substantially below10%, taken as a percentage of the amount of compound of formula (V), andpreferably below 5 or, still better, below 2%. Usually the best methodsfor making the compound of formula (V) provide the product with lessthan 0.5% contamination and frequently no benzal isomer can be detectedat all with analytical methods sensitive to even as low as 0.33%admixture. It has, on the other hand, been observed that contaminationat or above the 10% level adversely affects the yield and quality of thefinal benzylpyrimidine product, and the appearance of purple or yellowdiscolourisation may aggravate the difficulties, especially isolation ina pure form, an essential requirement when the product is to be usedclinically, there therefore being necessary many tedious, time-consumingand accordingly expensive purification steps.

As previously defined Ar is an optionally substituted phenyl group informula (V). The β-amino group Nr⁵ R⁶ is an aliphatic, heterocyclic oraromatic amino group, and can have only one hydrogen atom for R⁵ and R⁶.In general it may be stated that, as a free amine, HNR⁵ R⁶ is preferredto have a Pka value not lower than about 0, and also most preferably nothigher than about 6.

In particular, it is especially preferred that the NR⁵ R⁶ group is aprimary anilino group (e.g. aniline, o and p -toluidinep-anisidine,p-chloroaniline, 2,5 and 3,4 - dichloroanilines). The phenylring of this group may be optionally substituted with one or moresubstituents such as halogen atoms, and alkyl and alkoxy groups, but theunsubstituted anilino group is, however, particularly preferred.

The NR⁵ R⁶ group may also be a primary amino group other than theaforesaid primary anilino group, such as a monoalkylamino, benzylamino,or naphthylamino, preferably α-β-naphthylamino group; or may be asecondary amino group, such as adialkylamino,N-ethyl-anilino,pyrrolidino, piperidino, N-methylanilino ora piperazino group, or most preferably the morpholino group.

In particular the invention provides compounds of formula (VIII), in aform substantially free from contamination with theβ-amino-4-benzylidene-propionitrile isomer, as hereinbefore defined:##STR6## wherein the group --NR⁵ R⁶ is as hereinbefore defined withreference to a compound of formula (V), and R¹, R², R³ and R⁴ are thesame or different and each is a hydrogen or a halogen atom, an alkyl,alkoxy, or benzyloxy group, or R³ and R⁴ taken together may be amethylendioxy group when both R¹ and R² are hydrogen atoms. Preferablythe whole amino group Nr⁵ R⁶ comprises not more than 12 carbon atoms.

All of the above compounds of formula VIII are convertible to benzylpyrimidines and such pyrimidines are useful as antibacterials.

In formulae (V) and (VIII), and elsewhere in this application each ofthe alkyl or alkoxy groups in the substituents may have from 1 to 4carbon atoms, e.g. they may be methyl, ehtyl, propyl or butyl groups,including normal, iso or tertiary branched forms, and correspondingalkoxy groups. Each of the halogen atoms may be represented by achlorine, bromine, fluorine or iodine atom.

More particularly the para-position of the phenyl group may besubstituted with a benzyloxy, but preferably an alkoxy group, such as amethoxy group, especially with a similar or identical alkoxysubstitution at one or advantageously both adjacent positions on thephenyl ring. As another possibility alkoxy, e.g. methoxy substitution,in such positions may be combined with an alkyl, e.g. methyl,substitution at the ortho-position of the phenyl group.

The compounds of formulae V (or VIII) fall into two classes A and Bdependent on their reactivity towards guanidine. ##STR7##

Wherein Ph is an aryl group of 6 to 12 carbon atoms which may besubstituted in one, two, or three positions with lower alkyl, loweralkoxyl, and halogen, preferably chlorine and where the R₁ -R₄ aredefined as previously and lower alkyl halogen and lower alkoxyl are aspreviously defined. Compounds of type VIII A react readily withguanidine in e.g. solvent lower alcohol solution to form2,4-diamino-5-benzylpyrimidines in good yield. Advantageously thereaction is conducted at the reflux temperature of the solution, butuseful rates are found at lower temperatures down room temperatures.These compounds are consequently preferred.

The compounds of formula VIII wherein R₅ is alkyl or aryl and R⁶ isalkyl and may also be hydrogen when R₅ is alkyl and Nr₅ -R₆ ##STR8## mayalso be cyclic amino such as morpholino, piperidino and pyrrolidino,react only slowly with guanidine base, so that periods of 1-2 weekswould be required for complete reaction. They can be converted topyrimidines by reaction with guanidine carbonate in a polar aproticsolvent (as defined below but preferably DMSO) at an elevatedtemperature. This reaction is slow below 140° C but goes rapidly atabout 160° C or above.

The compounds according to formula (V) or (VIII), respectively, may beprepared by a wide variety of methods. The actual choice between thesemethods in any particular instance depends primarily on the reactivityof the compound obtained, and the further processing to which it may besubjected to provide compounds such as pyrimidines of clinical utility,the further processing being itself governed to a great extent by thenature of the amino group Nr⁵ R⁶, this acting as a leaving group in thefurther reactions.

Compounds according to formula (V) or (VIII) can be prepared by a methodprovided by the present invention, which comprises reacting thecorresponding benzaldehyde with the corresponding β-aminopropionitrilein the presence of a base in a polar aprotic solvent compatible with anddissolving both reactants.

Polar aprotic solvents suitable for the purpose includehexamethylphosphoramide and N,N-dimethylacetamide, but best results havebeen obtained with dimethylsulphoxide as the solvent. Bases required forthe reaction include the hydroxide, the alkoxides especially the loweralkoxides, preferably the methoxide or tert.-butoxide anions, and themethylsulphinyl carbanion, used in association with a suitable cation,such as an alkali metal (e.g. sodium or potassium or a quaternaryammonium cation (e.g. N-benzyl-N,N,N-trimethylammonium).

Advantageously, the amount of base can be considerably reduced to"catalytic amounts", i.e. effective quantities of less than about 0.3molar equivalent calculated on the aldehyde used, particularly attemperatures above 60° C, preferably between 90° C and 130° C. Forinstance, very good yields have been obtained in this manner usingdimethylsulphoxide as the solvent.

Very satisfactory yields have also been obtained, for instance, withβ-primary anilino-sustituted compounds with 0.5 to 2 molar equivalentsof the base at room (about 20° C) or slightly elevated temperature up toabout 60° C in the solvent. Dimethylsulphoxide may be replaced underthese conditions as well as by other polar aprotic solvents, expeciallyhexamethylphosphoramide. It has been found most advantageous to uset-butoxide as the base in the form of the potassium salt indimethylsulphoxide for the preparation of β-anilino- substitutedcompounds whilst, for instance, the β-morpholino-analogue may bepreferred to be formed in the presence of sodium methoxide in the samemedium.

Yet further methods provided by the present invention may be used toobtain selected or preferred ranges of compounds within the scope offormula (V) or (VIII). Accordingly, a method is provided for preparingsuch compounds, wherein the β-amino group Nr⁵ R⁶ is a primary anilinogroup optionally substituted in the phenyl ring, as hereinbeforedefined, which comprises reacting the corresponding benzaldehyde withthe corresponding β-primary-anilino-propionitrile. Preferably thereaction is carried out in a polar non-aprotic solvent compatible withand dissolving the reactants in the presence of a base. Conveniently analkanol may be used for the purpose, and the reaction is desirablycarried out at elevated temperatures, say between 40° and 80° C. Thepreferred alkanol is methanol, particularly when the reactantbenzaldehyde is substituted with one or more methoxy groups, since it ispossible for exchange to take place between the solvent and thesubstituents. Bases already listed in relation to the other preparatorymethods are again applicable, and may, for instance, be used in aquantity molar equivalent calculated on the aldehyde, especially whenthe reaction is carried out at the lower end of the indicatedtemperature range.

Compounds according to formula (V) or (VIII) can also be prepared byreacting the corresponding β-hydroxy-β-phenethylmethylsulphone orsulphoxide with the corresponding β-amino-propionitrile. Very preferablythe reactions carried out in the presence of a base in a polarnon-aqueous solvent compatible with and dissolving both reactants ofelevated temperature above 30° C. The solvent may be an alkanol, such asmethanol, ethanol or isopropanol, or most conveniently a polar aproticsolvent such as exemplified above. The base is preferably sufficientlystrong on its own for a significant amount of the sulphone or sulphoxidereactant to be converted into the anionic form. Again hydroxides oralkoxides, preferably methoxide or t-butoxide, in the form of an alkalimetal salt, have been found very convenient for the purpose. The methodis especially suitable for making Type VIII A.

The required β-hydroxy-β-phenethyl-methylsulphone or sulphoxide for theabove method, may conveniently be provided by a process described in theprovisional specification of British Patent Application No. 25171/69.This process comprises the steps of reacting an appropriatelysubstituted benzoic acid ester with dimethyl sulphone or dimethylsulphoxide preferably in the presence of a base, and selectivelyreducing the so obtained acetophenone methylsulphone or methylsulphinylderivative, for instance, with a suitable reducing agent e.g.(borohydride or with aluminium isopropoxide).

The above defined group of β-primary-anilino-α-benzylacrylonitriles canalso be prepared by a method which comprises reacting the correspondinganiline, generally in the form of an acid addition salt, with a compoundof formula (V) or (VIII) carrying an amino substituent which has, as thefree amine HNR⁵ R⁶, a pKa value higher by at least about 3 to 4 unitsthan that of the aniline used for reaction. For instance, a morpholinosubstituent may, in this manner, be directly replaced by an anilinosubstituent, morpholine having a pKa value of about 8.6 and the anilinegenerally about 4 to 5. Preferably the reaction is carried in a polarnon-aqueous solvent system, for instance, ethanol or glacial aceticacid, at reflux temperatures.

The compounds VIII A are also preparable by reaction of PhNH₂ withβ-hydroxy-α-benzylacrylonitriles: ##STR9##

This reaction is conveniently carried out in an organic solvent such asbenzene or a lower alcohol or without solvent and where Ph is aspreviously defined or PhNH₂ could also be Nr⁵ R⁶ where this is aspreviously defined.

The β-hydroxy-α -benzylacrylonitriles are prepared in exemplary fashionby acidification of a partly aqueous solution of a compound of type VIIIB wherein R₅ and R₆ are not aromatic. For this variation in aqueousalcohol VIII B is converted to the hydroxy compound X almostinstantaneously and in nearly quantitative yield.

The product may then be extracted with an organic solvent from theaqueous medium and reacted with a different amine to obtain a compoundaccording to formula (V) or (VIII). There is little or no tendency toisomerize to the `benzal` form during these manipulations.

Such a conversion from one amino derivative to another may be achievedin a very high yield, in many instances above 90% in both steps, and theproduct so obtained can be reacted to form other materials such asbenzylpyrimidines in a quality and yield often even better than thatprovided by using the original β-amino-derivative.

In addition, this method may be very advantageous for preparing certainβ-amino-α-benzylacrylonitriles, especially in cases where the Nr⁵ R⁶group is basic but only weakly basic anilino group, e.g.-chloro-anilino. In such instances, there are sometimes difficulties inpreparing the corresponding β-anilino-propionionitrile for reaction withthe benzaldehyde.

The β-hydroxy-α-benzylacrylonitriles may also be used as intermediatesfor further syntheses, and can, for instance, be alkylated to providethe appropriate β-alkoxy-α-benzylacrylonitrile, substantially free fromthe `benzal` isomer or acetal. The benzyl compound so formed and in suchpurity is also eminently suitable as a starting material for thesynthesis of benzylpyrimidines, and provides the latter in asubstantially increased yield and at a better quality than the mixtureof benzyl and benzal isomers, or the benzal isomer alone, of the methoddescribed in British Patent Specification No. 957,797.

Compounds according to formula (V) or (VIII), wherein the β-amino groupNr⁵ R⁶ is a primary amino group other than anilino, or is a secondaryamino group, can also be prepared according to the present invention byreacting the corresponding β-alkoxy-α-benzylidenepropionitrile with anexcess of the appropriate amine in the presence of a base in an alkanol.Suitable bases are again those already listed for other methods.Preferably the base is the alkoxide corresponding to the solvent. Forinstance, a β-methoxide-α-benzylidenepropionitrile may be so convertedwith morpholine, in methanol containing sodium methoxide, to thecorresponding β-morpholino-α-benzylacrylonitrile.

The above group of compounds according to formula (V) or (VIII), whereinthe β-amino-group NR⁵ R⁶ is other than the anilino group, can moreoverbe prepared according to the present invention by isomerising thecorresponding β-amino-α-benzylidene-propionitrile isomer with a base ina polar aprotic solvent. Under these conditions the `benzal` isisomerised into the `benzyl` form, there appearing to be little or no`benzal` isomer after the process. Suitable aprotic polar solvents andbases are as hereinbefore described with reference to other reactions,and the most preferred solvent is again dimetylsulphoxide and the mostconvenient bases are the methoxide and t-butoxide anions. Normally thereis at least about 0.01, preferably about 0.1 molar concentration of basepresent in the solvent, and often not more than about 1 molarconcentration, though as high as 2 or even 4 molar concentrations may beused. The quantity of solvent is not critical though there is preferablysufficient throughout the isomerisation to dissolve the nitrile. Theisomerisation can be effected at room temperature but is mostconveniently carried out in the presence of heat, particularly goodyields obtained when it is carried out at a temperature above about 20°C. and up to about 75° C. or even higher. The method has been verysuccessfully applied to β-morpholino-α-benzylidene-propionitriles, inparticular to those having a 3,4-dimethoxy or3,4,5-trimethoxy-benzylidene group.

The starting `benzal` isomer, i.e. the appropriateβ-amino-α-benzylidene-propionitrile, for the purposes of the abovereaction, can advantageously be prepared by reacting the correspondingbenzaldehyde with the corresponding β-aminopropionitrile in an alkanolin the presence of a "catalytic amount" of a base, in the sensehereinbefore used in the present specification, which means an effectivequantity of less than 0.3 molar equivalent calculated on the aldehydereagent.

Alkanols in this reaction are generally lower alkanols, having from 1 to4 carbon atoms, methanol being particularly preferred. Suitable basesare again those already suggested in connection with base catalysedcondensation reactions, but methoxides and tert.-butoxides, particularlythe former, are preferred for the present purpose. Best results may beobtained at elevated temperatures, and it is particularly preferred tocarry out the reaction at reflux temperatures.

As already indicated, the optimum route for preparing any particularcompound according to formula (V) or (VIII) may comprise a combinationof a number of the above processing possibilities, depending primarilyon the type of amino NR⁵ R⁶ group required. For instance,β-primary-anilino-α-3',4',5'-triemthoxy-benzylacrylonitrile has certainespecial advantages as an intermediate for the preparation oftrimethoprim. Thus, the reaction of guanidine withβ-primary-anilino-α-benzylacrylonitriles generally proceeds appreciablyfaster than that with other β-amino derivatives as defined by formula(V) or (VIII).

The β-anilino-intermediate can moreover be produced readily without any`benzal` isomer detectable by standard analytical methods, and can befurther processed to 2,4-diamino-5-benzylpyrimidines in a very highyield there being little or no polymer formation at all. It is mostnoteworthy that the reaction with guandine is readily effected undermild conditions, and both the preparation of the intermediate and thefurther processing may be completed within hours rather than weeks.

Whilst β-primary-anilino-α-benzylacrylonitriles may be readily preparedby a wide variety of advantageous methods, the choice in any paritcularinstance depends partly upon the availability of the starting material,and, for instance, β-anilino-propionitrile, when prepared from anilineand acrylonitrile, usually requires isolation and purification beforeuse. In contrast, the corresponding β-morpholinopropionitrile can bereadily formed and need not be isolated. Furthermore, in cases oftrimethoxy-substituted benzyl derivatives, and base catalysed reactions,the cheaper and more widely available sodium methoxide is preferred formorpholino-derivatives, whilst the more expensive potassium t-butoxidegenerally gives best results for anilino-compounds. It may therefore onoccasion be advantageous to prepare the morpholino-intermediate firstand convert this into the corresponding anilino derivative to obtainoptimum results.

According to the present invention in a further aspect there is provideda method of preparing 2,4-diamino-5-benzylpyrimidines as shown informula IX which are useful as antibacterials, wherein the benzyl groupcomprises an optionally substituted phenyl group, by reacting thecorresponding β-aminio-α-benzylacrylonitrile of formula (V),substantially free from contamination with theβ-amino-α-benzylidene-propionitrile isomer, as hereinbefore defined,with guanidine. In particular a method is provided of preparing acompound of formula (IX) ##STR10## which comprises reacting a compoundof formula (VIII) substantially free from contamination with theβ-aminio-α-benzylidenepropionitrile isomer, as hereinbefore defined,with guanidine; in formula (IX) R¹,R²,R³ and R⁴ are as defined forformula (VIII). It has been found that the pyrimidine products areobtained in a satisfactorily high yield as well as without contaminationwith polymers and coloured impurities. These aspects are of criticalimportance as indicated hereinbefore, since contemporary requirementsfor the purity of pharmaceutical products are very stringent and theproducts must be manufactured in a very pure form and, of course, at aresonable cost. Both these necessities are now more readily attainable,as a result of the present invention, for the benzylpyrimidines.

To obtain 5-benzylpyrimidines having particularly high activity, orpotentiating properties, the para position of the phenyl group ispreferably substituted with an alkoxy, i.e. methoxy group, especially incombination with a similar substitution at one or both adjacent metapositions. Such substitutions may also be present when at least one ofthe ortho-positions is occupied by a lower alkyl group, such as methyl.The pyrimidines are then trimethoprim, diaveridine, ormetoprim andanalogues thereof.

For the purposes of obtaining 5-benzylpyrimidines or in particular thoseof formula (IX) preferably having the above mentioned specificsubstituents, the appropriate β-anilino-derivatives have been foundparticularly useful. Advantageously such an amine is reacted withguanidine, conveniently in a lower alcohol solvent, for example,methanol, ethanol, or isopropanol, at elevated temperatures. It isparticularly preferred that the reaction is carried out at the refluxtemperature of the reaction mixture, but useful routes are found attemperatures down to room temperatures. It has been found specificallythat the reaction takes place very readily, taking hours rather thanweeks for completion.

Although the reactivity with guanidine, ofβ-aminio-α-benzylacrylonitriles of formula (V) or (VIII), other thanthose having a β-primary-anilino group, such as the morpholinoderivatives is lower, particularly in alkanols, it has been found thatthis can be increased and the yield substantially improved if theguanidine is employed in the form of the carbonate in a polar aproticsolvent, as hereinbefore described with reference to other methods, e.g.especially dimethylsulphoxide or hexamethylphosphoramide. Best resultshave been obtained in these particular cases with dimethylsulphoxide ator near 160° C, and, if the previous reaction step has also been carriedout in the same medium the -βamino-α-benzylacrylonitrile intermediateneed not be isolated, although isolation is usually preferred sincepurer benzylpyrimidine is obtained in this manner.

All end products provided in the above manner have either antibacterialactivity or potentiating properties, although the degree of suchactivity and potentiating effect may vary according to substitution andthe purpose for which these compounds are employed. Moreover, theproducts may themselves be used as starting materials to produce otherderivatives and analogues by further reactions with functional groupsthereon. Thus benzyloxy-benzyl-derivatives may, for instance, beconverted into the corresponding hydroxy-benzyl-derivatives byhydrogenation, or any hydroxy-benzyl-derivatives alklated to provide therequired alkoxy-benzyl-substituted compounds.

According to the present invention, therefore, there are provided:

I. N=substituted-β-amino-α-benzylacrylonitrile compounds according toformula (V), or, in particular, formula (VIII), substantially free fromcontamination with β-aminio-α-benzylidenepropionitrile, as hereinbeforedescribed;

ii. the various methods of preparing β-aminio-α-benzylacrylonitriles offormula (V) or (VIII), as hereinbefore described;

iii. the various methods of converting such aβ-aminio-α-benzylacrylonitrile into a different compound of the sameclass with respect of the β-amino-substitution, as hereinbeforedescribed;

iv. N-substituted β-amino-α-benzylacrylonitriles whenever prepared by amethod defined under either of paragraphs (ii) and (iii), ashereinbefore described;

v. β-hydroxy-α-benzylacrylonitriles substantially free fromcontamination with isomers, as hereinbefore described;

vi. the methods of preparing the compounds defined under paragraph (v);

vii. the methods of preparing 5-benzylpyrimidines by using compounds orproducts of methods, according to any one of paragraphs (i) to (vi), ashereinbefore described;

viii. 5benzylpyrimides whenever prepared by a method including stepsaccording to any one of paragraphs (ii), (iii), (vi) and (vii).

The present invention, in each of the above aspects, is particularlypreferred when the phenyl group is a 3,4-dimethoxy, 3,4,5-trimethoxy or2-methyl-4,5-dimethoxy group, since there are then produced theespecially valuable compounds diaveridine, trimethoprim or ormetoprim,or the respective intermediates therefor.

The following Examples illustrate the invention:

EXAMPLES Example 1

3,4,5 - Trimethoxybenzaldehyde (98g.), β - anilinopropionitrile (85g.),and dimethylsulfoxide (175 ml.) were heated together to 125° C. Asolution of sodium methylate (5g.) in methanol (50ml.) was graduallyadded and in so doing the reaction temperature rose to 130° C, and thistemperature was maintained for a further 17 minutes. The reactionmixture was chilled; water was added to a persistent haze; seeds orβ-anilino - α -3,4,5 - trimethoxybenzylacrylonitrile were added; and themixture was stirred at 25° C until precipitation was copious. Additionalwater (400ml.) was added, and the product was collected by filtrationand reslurried in ice water (600ml.). The collection and reslurryprocedures were repeated using cold (˜5° C) denatured alcohol (320ml.),and the crystalline β-anilino - α -3,4,5 - trimethoxybenzylacrylonitrilewas finally collected; washed with cold denatured alcohol (40ml.), andhexane (100ml.). Wt. =115g. (71%; 98% pure by U.V. assay) m.p. 132°-133° C (recrystallised from methanol).

Example 2

3,4,5-Trimethoxybenzaldehyde (49 g.), βanilinopropionitrile (40 g.), anddimethylsulfoxide (85 ml.) were heated together to 130° C, and asolution of potassium hydroxide (2.5 g.) in methanol (12.5 ml.) wasadded over a 35 min. period. The temperature of the reaction wasmaintained at 130°-135° C for an additional 30 min., and the reactionmixture was then treated as in Example 1 to giveβ-anilino-α-3,4,5-trimethoxybenzylacrylonitrile as a crystalline solid.Wt.=57 g. (70%).

Example 3

3,4,5-Trimethoxybenzaldehyde (117.5 g; 0.6 mole), β-anilinopropionitrile(101 g.; 0.69 mole), and dry distilled dimethylsulfoxide (348 ml.) wereheated together to 40° C until solution was complete. The mixture waschilled to 12° C and a solution of potassium t-butoxide in t-butanol(13.6%; 491 ml.; 0.6 mole) was added over the course of about 10 min,such that the final temperature was about 30° C. The temperature wasraised to 40° C and maintained for 1 hour. t-Butanol was then strippedfrom the reaction using vacuum to a final pot temperature of 55° C. Theresidue was chilled to 30° C and water (100 ml.) and denatured ethanol(50 ml.) added. The mixture was seeded and after obvious crystallisationmore ice/water (500 ml.) and denatured ethanol (75 ml.) were added. Whenthe final temperature of the mixture was 5°-10° C the crystallineβ-anilino-α-3,4,5-trimethoxybenzylacrylonitrile was collected, andwashed with a mixture of cold water/denatured ethanol (85:15; 600 mol.).Wt=181.7 g. (94% pure by U.V. assay; yield 88%).

Example 4

3,4-Dimethoxybenzaldehyde (88 g.) β-anilinopropionitrile (82.5 g.),dimethylsulfoxide (160 ml.), and sodium methylate were heated togetherat 95° C for 21/2hr. The reaction mixture was then chilled to 25° C anddiluted with isoproply alcohol (40 ml.) and water. When crystallisationwas obvious further water (200 ml.) was added. The mixture was cooled to5° C and crystalline β-anilino-α-3,4-dimethoxybenzylacrylonitrile wascollected and washed with cold water/isopropyl alcohol (1:1) Wt.=99 g.(61%) m.p. 153° -154° C (recrystallised from denatured alcohol).

Example 5

Piperonaldehyde (45 g.), β-anilinopropionitrile (52 g.) anddimethylsulfoxide (96 ml.) were heated together to 120° C and a solutionof sodium methylate (2.5 g.) in methanol (12 ml.) was added over a 5min. period. The temperature was maintained at 115° -120° C for 1 hr.and the mixture was then poured into ice-water. The resulting gum wascollected by decantation and was likewise washed with water (2 × 100ml.). Methanol (100 ml.) was then added and the mixture was heated untilsolution was complete. Cooling to 5° C gaveβ-anilino-α-piperonylacrylonitrile as a crystalline solid which wascollected, and washed with cold methanol, ether, and pentane. Wt.=45 g.(54%) m.p. 150.5° -151° C (recrystallised from methanol).

Example 5a

The procedure of Example 3 was repeated using3,4-dimethoxy-5-bromobenzaldehyde (78 g.) and gaveβ-anilino-α-3,4-dimethoxy-5-bromobenzylonitrile. Wt.=62 g. (52%) m.p.151°-154° C.

Example 6

Sodium methylate (5.4 g.) in t-butanol (50 ml.) was slowly treated witha solution of 3,4,5-trimethoxybenzaldehyde (20 g.) andβ-(p-methylanilino)-propionitrile (17.5 g.) in dimethylsulfoxide (50ml.). The mixture was stirred at 45° C for 1 hour and the alcohol thenremoved in vacuo (bath temperature ≯50° C). The mixture was poured intoice-water and the crude product collected and recrystallised frommethanol to giveβ-(p-methylanilino)-α-3,4,5-trimethoxybenzylacrylonitrile. Wt.=30 g.(89%) m.p. 150°-151° C (recrystallised from methanol).

Example 7

The procedure of Example 6 was repeated using β-(p-chloroanilino)propionitrile (20 g.) in place of β-(p-methylanilino) propionitrile. Wt.of recrystallisedβ-(p-chloroanilino)-α-3,4,5-trimethoxybenzylacrylonitrile =]24 g. (67%)m.p. 172°-173° C (recrystallised from methanol).

Example 8

The procedure of Example 6 was repeated using β-(p-methoxyanilino)propionitrile (19.5 g.) in place of β-(p-methylanilino) propionitrile.Wt. of recrystallisedβ-(p-methoxyanilino)-α-3,4,5-trimethoxybenzylacrylonitrile = 11 g. (33%)m.p. 125°-125° C (recrystallised from methanol).

Example 9

2-Methyl-4,5-dimethoxybenzaldehyde (18 g.), dimethylsulphoxide (35 ml.),sodium methoxide (1.0 g.), and β-anilinopropionitrile were heatedtogether at 95° C for 11/2 hr. The mixture was then poured intoice-water (150 g.), and the resulting solid collected by decantation.The crude product was recrystallised from methanol (100 ml.) and theresulting β-anilino-α-(2-methyl-4,5-dimethoxybenzyl) acrylonitrile wascollected, and washed with methanol and hexane. Wt. = 19 g. (60%) m.p.117°-119° C (recrystallised from ethanol/methanol).

Example 10

p-Benzyloxybenzaldehyde (25 g.), β-anilinopropionitrile (22 g.), anddimethylsulphoxide (25 ml.) were heated together to 95° C, and a slurryof sodium methoxide (1 g.) in dimethylsulphoxide (20 ml.) was carefullyadded such that the temperature rose to 105° C. The mixture was heatedto 125°-130° and held at that temperature for 11/2 hr. The reactionmixture was poured into ice-water (500 ml.), and the resulting solid wascollected and washed by decantation. The crude product was slurried incold ethanol to give β-anilino-α-(p-benzyloxybenzyl) acrylonitrile. Wt.= 27 g.

Example 11

β-Morpholinopropionitrile (47 g.), sodium methoxide (2 g), anddimethylsulphoxide (40 ml.) were heated together to 65° C, and asolution of 3,4,5-trimethoxybenzaldehyde (50 g.) in dimethylsulphoxide(40 ml.) was added slowly such that the temperature rose to 70°-75° C.After 3 min. at this temperature the mixture was cooled to 30° C, andisopropyl alcohol (30 ml.) and water sufficient to creat a persistenthaze were added. The mixture was seeded and, after crystallisation wasobvious, water (80 ml.) was added. Crystallineβ-morpholino-α-3,4,5-trimethoxybenzylacrylonitrile was collected andwashed with isopropyl alcohol (50 ml.). Wt. = 73.5 g. (89%) m.p.115°-117° C (recrystallised from methanol).

Example 12

3,4,5-Trimethoxybenzaldehyde (20 g.), β-N-methylanilinopropionitrile (18g.), dimethylsulphoxide (40 ml.), and sodium methoxide (1 g.) wereheated together at 110°-115° C for 1.5 hr. The mixture was poured intoice-water (800 ml.) and the crude product which precipitated gavecrystalline β-N-methylanilino-α-3,4,5-trimethoxybenzylacrylonitrileafter a slurry in methanol (50 ml.). Wt. = 17 g. (50%) m.p. 121°-122° C(recrystallised from methanol.

Example 13

3,4,5-Trimethoxybenzaldehyde (50 g.), β-piperidinopropionitrile (40 g.),di-methylsulphoxide (60 ml.), and sodium methoxide (2 g.) were reactedtogether at 75° C for 20 min. and on work-up gaveβ-piperidino-α-3,4,5-trimethoxybenzylacrylonitrile. Wt.=40 g. (50%) m.p.92°-93° C (recrystallised from methanol).

Example 14

3,4,5-Trimethoxybenzaldehyde (25 g.), β-pyrrolidinopropionitrile (20g.), dimethylsulphoxide (25 ml.) and sodium methoxide (1 g.) werereacted together at 75° C for 10 min., and on work-up gaveβ-pyrrolidino-α-3,4,5-trimethoxybenzylacrylonitrile. Wt.=28 g. (75%)m.p. 123°-124° C (recrystallised from methanol).

Example 15

3,4,5-Trimethoxybenzaldehyde (25 g.), β-N-dimethylaminopropionitrile (16g.), dimethylsulphoxide (45 ml.), and sodium methoxide (1 g.) werereacted together at 70° C for 10 min., and on work-up gaveβ-dimethylamino-α-3,4,5-trimethoxybenzylacrylonitrile. Wt.=25 g. (73%)m.p. 122°-123° C (recrystallised from methanol).

Example 16

3,4,5-Trimethoxybenzaldehyde (50 g.), β-benzylaminopropionitrile(45 g.),dimethylsulphoxide (80 ml.), and sodium methoxide (2 g.) were heatedtogether at 100° C for 2 hr., and on work-up gaveβ-benzylamino-α-3,4,5-trimethoxybenzylacrylonitrile. Wt.=32 g. (37%)m.p. 130.5°-131° C (recrystallised from methanol).

Example 17

3,4,5-Trimethoxybenzaldehyde (25 g.), β-morpholinopropionitrile (20 g.),sodium methoxide (2 g.), and N,N-dimethylacetamide (25 ml.) were reactedtogether at 90°-95° C for 11/2 hr., and on work-up gaveβ-morpholino-α-3,4,5-trimethoxybenzylacrylonitrile. Wt.=15 g. (37%).

Example 18

β-Morpholinopropionitrile (40 g.), dimethylsulphoxide (40 ml.), andsodium methoxide (2 g.) were heated together at 70° C and a solution of3,4-dimethoxybenzaldehyde (44 g.) in dimethylsulphoxide (40 ml.) wasadded. The reaction was held at 75°-80° C for 15 min., and thenworked-up as in Example 11 to give crystallineβ-morpholino-α-3,4-dimethoxybenzylacrylonitrile. Wt.=41 g. (57%) m.p.130°-131° C (recrystallised from methanol).

Example 19

The procedure of Example 18 was repeated usingβ-dimethylaminopropionitrile (28 g.) in place ofβ-morpholinopropionitrile, and on work-up gaveβ-dimethylamino-α-3,4-dimethoxybenzylacrylonitrile. Wt.=31 g. (50%) m.p.85°-86° C (recrystallised from methanol).

Example 20

β-Morpholinopropionitrile (20 g.), dimethylsulphoxide (30 ml.), andsodium methoxide (1 g.) were heated together at 80° C and a solution ofpiperonaldehyde (19 g.) in dimethylsulphoxide was added. The mixture wasreacted at 80° C for 15 min., and on work-up gaveβ-morpholino-α-piperonylacrylonitrile. Wt.=21 g. (61%) m.p. 85°-85.5° C(recrystallised from methanol).

Example 21

The procedure of Example 20 was repeated using3,4-dimethoxy-5-bromobenzaldehyde (31 g.) in place of piperonaldehydeand on work-up gaveβ-morpholino-α-3,4-dimethoxy-5-bromobenzylacrylonitrile. Wt.=28 g. (60%)m.p. 94.5°-95° C (recrystallised from denatured ethanol.

Example 22

β-Hydroxy-α-3,4,5-trimethoxybenzylacrylonitrile (132 g.), obtained ashereinafter described in Example 62, was refluxed for 10 min. in benzenecontaining aniline (50 g.). The solvent was removed by evaporation invacuo to provide crystallineβ-anilino-α-3,4,5-trimethoxybenzylacrylonitrile (165 g.; virtuallytheoretical yield).

Example 23

A solution of morpholine (10 ml.) andβ-hydroxy-α-3,4,5-trimethoxybenzylacrylonitrile (24.9 g.) in ethanol(100 ml.) was refluxed for 30 min. When cooled the reaction gaveβ-morpholino-α-3,4,5-trimethoxybenzylacrylonitrile. Wt.=27 g. (85%) m.p.116°-117° C.

Example 24

β-Hydroxy-β-3,4,5-trimethoxyphenethylmethylsulphone (29 g.),β-anilinopropionitrile (16.5 g.), and dimethylsulphoxide (40 ml.) wereheated together to 40° C,, and a solution of potassium-t-butoxide int-butanol (13.6%; 83 ml.) was carefully added. The temperature wasmaintained at 45° C for 1 hr. Alcohol was then removed from the reactionmixture by vacuum evaporation and the residue was poured into ice-water(200 ml.). The crude crystalline product was collected andrecrystallised from ethanol to giveβ-anilino-β-3,4,5-trimethoxybenzylacrylonitrile. Wt.=26 g. (afterwashing with ethanol and hexane; 80%).

Example 25

The procedure of Example 24 was repeated using hexamethylphosphoramide(40 ml.) in place of dimethylsulphoxide, and on work-upβ-anilino-α-3,4,5-trimethoxybenzylacrylonitrile was obtained. Wt.=26 g.(80%) m.p. 126°-128° C.

Example 26

β-Hydroxy-β-3,4,5-trimethoxyphenethylmethylsulphone (5 g.),β-anilinopropionitrile (3 g.) dimethylsulphoxide (20 ml.), and asolution of potassium hydroxide in methanol (20%; 2 ml.) were reactedtogether at 90°-95° C for 20 min. Work-up gaveβ-anilino-α-3,4,5-trimethoxybenzylacrylonitrile (3 g.; 53%). m.p.126°-129° (recrystallised (recrystalised from ethanol).

Example 27

The procedure of Example 26 was repeated using hexamethylphosphoramide(20 ml.) in place of dimethylsulphoxide and on work-up gaveβ-anilino-α-3,4,5-trimethoxybenzylacrylonitrile (2 g.; 36%) m.p.125°-127° C (recrystallised from ethanol).

Example 28

The procedure of Example 26 was repeated using sodium methoxide (0.5 g.)in place of potassium hydroxide in methanol, and on work-up gaveβ-anilino-α-3,4,5-trimethoxybenzylacrylonitrile. Wt.=3 g. (54%) m.p.128°-130° C.

Example 29

β-Hydroxy-β-3,4,5-trimethoxyphenethylmethylsulphone (10 g.),β-anilinopropionitrile (5.1 g.), hexamethylphosphoramide (20 ml.), andsodium methoxide (1 g.) were reacted together at 60° C for 30 min., andon work-up gave β-anilino-α-3,4,5-trimethoxybenzylacrylonitrile. Wt.=6g. (54%) m.p. 127°-129°C.

Example 30

The procedure of Example 28 was repeated using N,N-dimethylacetamide (25ml.) in place of dimethylsulphoxide, and on work-up gaveβ-anilino-α-3,4,5-trimethoxybenzylacrylonitrile. Wt.=2.5 g. (45%) m.p.125°-128° C.

Example 31

β-Hydroxy-β-3,4,5-trimethoxyphenethylmethylsulphoxide (5.4 g.),β-anilinopropionitrile (3 g.), dimethylsulphoxide (25 ml.), and sodiummethylate (0.5 g.) were reacted together at 90°-95° C for 1 hr. Themixture was then poured into ice-water; the solid collected; andrecrystallised from denatured ethanol to giveβ-anilino-α-3,4,5-trimethoxybenzylacrylonitrile. Wt.=2 g. (30%) m.p.125°-127° C.

Example 32

The procedure in Example 31 was repeated using potassium hydroxide (2g.) in methanol (5 ml.) in place of sodium methoxide, and on work-upgave β-anilino-α-3,4,5-trimethoxybenzylacrylonitrile. Wt.=2 g. (30%)m.p. 125°-128° C.

Example 33

The procedure in Example 31 was repeated using hexamethylphosphoramidein place of dimethylsulphoxide and sodium methylate (2 g.), and onwork-up gave β-anilino-α-3,4,5-trimethoxybenzylacrylonitrile. Wt.=2 g.(30%) m.p. 125°-129°C.

Example 34

The procedure in Example 31 was repeated using potassium-t-butoxide int-butanol (13.6%; 15 ml.) in place of sodium methoxide, and on work-upgave β-anilino-α-3,4,5-trimethoxybenzylacrylonitrile. Wt.=1 g. (15%)m.p. 128°-130° C.

Example 35

The procedure in Example 34 was repeated using hexamethylphosphoramide(25 ml.) in place of dimethylsulphoxide, and on work-up gaveβ-anilino-α-3,4,5-trimethoxybenzylacrylonitrile. Wt.= 1 g. (15%) m.p.123°-126° C.

Example 36

β-Morpholinopropionitrile (3.0 g.),β-hydroxy-β-3,4,5-trimethoxyphenethylmethylsulphone (2.9 g.), sodiummethoxide (0.3 g.) and hexamethylphosphoramide (6 ml.) were reactedtogether at 60°-65° C for 40 min., and then poured into ice-water (50ml.). The crude solid was collected by decantation and recrystallisedfrom ethanol (10 ml.) to giveβ-morpholino-α-3,4,5-trimethoxybenzylacrylonitrile. Wt.=2 g. (˜60%).

Example 37

The procedure in Example 36 was repeated using benzyltrimethylammoniumhydroxide in place of sodium methoxide and on work-upβ-morpholino-β-3,4,5-trimethoxybenzylacrylonitrile was obtained in 50%yield.

Example 38

3,4,5-Trimethoxybenzaldehyde (40 g.), β-anilinopropionitrile (44 g.),sodium methoxide (32 g.), and methanol were heated together under refluxfor 45 min. The reaction mixture was then poured into ice-water (200ml.) and the resulting thick oil was collected and washed bydecantation. Recrystallisation from ethanol gave crystallineβ-anilino-α-3,4,5-trimethoxybenzylacrylonitrile. Wt.=42 g. (afterwashing with ethanol and pentane; 64%).

Example 39

3,4-Dimethoxybenzaldehyde (41.5 g.), β-anilinopropionitrile (38.5 g.),sodium methoxide (40 g.) and methanol (200 ml.) were reacted underreflux for 3 hr. The solvent was then removed by evaporation in vacuoand the resulting paste was recrystallised from methanol to giveβ-anilino-α-3,4,-dimethoxybenzylacrylonitrile. Wt.=55 g. (75%) m.p.153°-154° C (recrystallised from ethanol).

Example 40

β-Morpholino-α-3,4,5-trimethoxybenzylacrylonitrile (318 g.), aniline(107 g.) and glacial acetic acid (69 g.) were heated together at 95° Cfor 45 min. Isopropanol (300 ml.) was then added and the mixture wascooled to 30° C; seeded; and treated with water (300 ml.) aftercrystallisation was obvious. Filtration gaveβ-anilino-α-3,4,5-trimethoxybenzylacrylonitrile. Wt.=296 g. (afterwashing with water and isopropanol; 91%).

Example 41

Aniline hydrochloride, from aniline (10 g.) and conc. hydrochloric acid(12 ml and β-morpholino-α-3,4,5-trimethoxybenzylacrylonitrile (30 g.)were reacted together in refluxing isopropanol (50 ml.) for 15 min.Water (25 ml.) was added and on cooling crystals ofβ-anilino-α-3,4,5-trimethoxybenzylacrylonitrile were obtained. Wt.=29 g.

Example 42

β-Methoxy-α-3,4,5-trimethoxybenzylidenepropionitrile (53 g.), obtainedaccording to method described in B.P. 957,797, morpholine (100 ml.),sodium methoxide (14 g.), and methanol (53 ml.) were heated together at90° C for 15 min. The solvent was removed by evaporation in vacuo andthe residue was poured into ice-water. The thick oil which separated wascollected and washed by decantation and on treatment with ether gavecrystalline β-morpholino-α-3,4,5-trimethoxybenzylacrylonitrile. Wt.=53g. (88%).

Example 43

3,4,5-Trimethoxybenzaldehyde (25 g.), β-morpholinopropionitrile (20 g.),methanol (50 ml.), and sodium methoxide (1 g.) were heated togetherunder reflux for 72 hr. Solvent was then removed in vacuo and theresidue was crystallised from diethylether (100 ml.) to giveβ-morpholino-α-3,4,5-trimethoxybenzylidenepropionitrile. Wt.=18 g. (44%)100.5°-102° C (recrystallised from methanol).

Example 44

3,4-Dimethoxybenzaldehyde (21 g), β-morpholinopropionitrile (22 g.),sodium methylate (1 g.) and methanol (50 ml.) were heated together underreflux for 20 hr. Work-up as in Example 43 gaveβ-morpholino-α-3,4-dimethoxybenzylidenepropionitrile. Wt.=25 g. (67%)m.p. 95°-97° C. (recrystallised from methanol).

Example 45

The procedure of Example 43 using β-piperidinopropionitrile (20 g.) gaveβ-piperidino-α-3,4,5-trimethoxybenzylidenepropionitrile. Wt.=32 g. (79%)m.p. 60°-62° C. (recrystallised from isopropanol).

Example 46

The procedure of Example 43 using β-pyrrolidinopropionitrile (20 g.)gave β-pyrrolidino-α-3,4,5-trimethoxybenzylidenepropionitrile as an oil.Wt.=37 g. (96%).

Example 47

The procedure of Example 43 using β-dimethylaminopropionitrile (18 g.)gave β-dimethylamino-α-3,4,5-trimethoxybenzylidenepropionitrile. Wt.=20g. (57%) m.p. 81°-83° C (recrystallised from methanol).

Example 48

Piperonaldehyde (30 g.), β-morpholinopropionitrile (40 g.), methanol (75ml.) and sodium methylate (1.5 g.) were heated together under reflux for20 hr. Solvent was removed in vacuo and the residue recrystallised fromether, after treatment with aqueous sodium bisulphite, to giveβ-morpholino-α-piperonylidenepropionitrile. Wt.=29 g. (53%) m.p. 80°-85°C (recrystallised from methanol).

Example 49

β-Morpholino-α-3,4,5-trimethoxybenzylidenepropionitrile (3 g.),dimethylsulphoxide (10 ml.) and sodium methoxide (0.1 g.) were heatedtogether at 50°-60° C for 10 min. Work-up gave crystallineβ-morpholino-α-3,4,5-trimethoxybenzylacrylonitrile. m.p. 115°-117° C.

Example 50

The procedure of Example 49 was repeated usingβ-dimethylamino-α-3,4,5-trimethoxybenzylidenepropionitrile (4 g.) and onwork-up gave β-dimethylamino-α-3,4,5-trimethoxybenzylacrylonitrile.Wt.=3.2 g. (80%) m.p. 119°-122° C (recrystallised from methanol).

Example 51

The procedure of Example 49 was repeated usingβ-piperidino-α-3,4,5-trimethoxybenzylidenepropionitrile (3.5 g.) and inwork-up gave β-piperidino-α-3,4,5-trimethoxybenzylacrylonitrile. Wt.=2.7g. (77%) m.p. 89°-92° C.

Example 52

β-Dimethylamino-α-3,4,5-trimethoxybenzylidenepropionitrile (2 g.),hexamethylphosphoramide (10 ml.), and sodium methoxide (0.05 g.) wereheated together at 30° C. Conversion toβ-dimethylamino-α-3,4,5-trimethoxybenzylacrylonitrile was complete in 1min. and this compound was obtained on work-up. Wt.=1 g. (50%) m.p.118°-120° C (recrystallised from methanol).

Example 53

β-Dimethylamino-α-3,4,5-trimethoxybenzylidenepropionitrile (2 g.),dimethylsulphoxide (10 ml.) and potassium-t-butoxide (0.05 g.) at 30°for 1 min. gave β-dimethylamino-α-3,4,5-trimethoxybenzylacrylonitrile.Wt.=1 g. (50%) m.p. 119°-121°C.

Example 54

β-Dimethylamino-α-3,4,5-trimethoxybenzylidenepropionitrile (4 g.),hexamethylphosphoramide (10 ml.) and potassium-t-butoxide (0.05 g.) at30° C for 1-2 min. gaveβ-dimethylamino-α-3,4,5-trimethoxybenzylacrylonitrile. Wt.= 3 g. (75%)m.p. 117°-119° C.

Example 55

β-Dimethylamino-α-3,4,5-trimethoxybenzylidenepropionitrile (2 g.),dimethylsulphoxide (10 ml.), and 3 drops of a saturated solution ofpotassium hydroxide in methanol at 40° C for 5 min. gaveβ-dimethylamino-α-3,4,5-trimethoxybenzylacrylonitrile Wt.=1.3 g. (65%)m.p. 118°-120°C.

Example 56

The procedure as in Example 55 using hexamethylphosphoramide in place ofdimethylsulphoxide in 2 min. gaveβ-dimethylamino-α-3,4,5-trimethoxybenzylacrylonitrile Wt.=1.8 g. (90%)m.p. 121°-123° C.

Example 57

The procedure as in Example 49 usingβ-pyrrolidino-α-3,4,5-trimethoxybenzylidenepropionitrile gaveβ-pyrrolidino-α-3,4,5-trimethoxybenzylacrylonitrile. m.p. 123°-124° C.

Example 58

The procedure as in Example 52 usingβ-morpholino-α-3,4,-dimethoxybenzylidene propionitrile gaveβ-morpholino-α-3,4-dimethoxyacrylonitrile. m.p. 127°-129° C.

Example 59

The procedure as in Example 49 usingβ-morpholino-α-piperonylidenepropionitrile (5.0 g.) gaveβ-morpholino-α-piperonylacrylonitrile. Wt.=4.5 g. (90%) m.p. 82°-84° C.

Example 60

The procedure as in Example 50 using N,N-dimethylacetamide in place ofdimethylsulphoxide gaveβ-dimethylamino-α-3,4,5-trimethoxybenzylacrylonitrile in 83% yield. m.p.121°-123° C.

Example 61

The procedure as in Example 52 using benzyltrimethylammonium hydroxidein place of sodium methoxide gaveβ-dimethylamino-α-3,4,5-trimethoxybenzylacrylonitrile in 86% yield. m.p.122°-123° C.

Example 62

β-Morpholino-α-3,4,5-trimethoxybenzylacrylonitrile (157 g.) was treatedwith conc. hydrochloric acid (75 ml.) in water (180 ml.) at 60° C for 15min. The reaction mixture was cooled, extracted with chloroform (100ml.; 75 ml.; 75 ml.), and the extracts were back-washed with water (75ml.). Removal of solvent gaveβ-hydroxy-α-3,4,5-trimethoxybenzylacrylonitrile as a thick oil. Wt.=125g. (theory).

Example 63

β-Hydroxy-α-3,4,5-trimethoxybenzylacrylonitrile (70 g.) in methanol (150ml.) at 10° C was treated with dimethylsulphate (39 g.). To the mixturewas then gradually added a solution of potassium hydroxide (20 g.) inmethanol (30 ml.) and water (12 ml.) and the reaction was then kept at10° C for 15 min. The mixture was next heated to 60° C for 15 min.; thencooled; and finally solvent was removed to a residue which was slurriedin water (100 ml.) and extracted into chloroform (2 × 80 ml.). Thechloroform extract, after back-washing with water (70 ml.), drying, andtreatment with charcoal, was evaporated to dryness to giveβ-methoxy-α-3,4,5-trimethoxybenzylacrylonitrile. Wt.=61 g. (80%).

Example 64

β-Anilino-α-3,4,5-trimethoxybenzylacrylonitrile (32 g.) and a solutionof guanidine hydrochloride (19 g.) and sodium methoxide (13 g.) indenatured ethanol (100 ml.) were heated under reflux for 21/2 hr.Solvent (31 ml.) was boiled off and the mixture was cooled to 5° C. Theresulting crystals of2,4-diamino-5-(3',4',5'-trimethoxybenzyl)pyrimidine were collected andwashed with denatured ethanol and acetone. Wt.=27 (94%) m.p. 198°-200°C.

Using methanol in place of denatured alchohol gave 2,4-diamino-5-(3',4',5'-trimethoxybenzyl)pyrimidine in 86% yield after 6 hr. reflux; withisopropanol the reaction was over in 2 hrs. and the yield was 78%.

Example 65

The product from Example 6 was converted to2,4-diamino-5-(3',4',5'-trimethoxybenzyl)pyrimidine by the procedure ofExample 64 in 2 hr. Yield=90%.

Example 66

The product from Example 7 was converted to2,4-diamino-5-(3',4',5'-trimethoxybenzyl)pyrimidine by the procedure ofExample 64 in 2 hr. Yield=90%.

Example 67

The product from Example 8 was converted to2,4-diamino-5-(3',4',5'-trimethoxybenzyl)pyrimidine by the procedure ofExample 64 in 41/2 hr. Yield=90%.

Example 68

The procedure of Example 64 was repeated usingβ-anilino-α-3,4-dimethoxybenzylacrylonitrile (29.4 g.) and gave2,4-diamino-5-(3',4'-dimethoxybenzyl)pyrimidine. Wt.=25.5 g. (98%) m.p.230°-233° C.

Example 69

The procedure of Example 64 was repeated usingβ-anilino-α-piperonylacrylonitrile (28 g.) and gave2,4-diamino-5-piperonylpyrimidine. Wt.=22 g. (89.5%) m.p. 252°-253° C(recrystallised from denatured alcohol).

Example 70

The procedure of Example 64 was repeated usingβ-anilino-α-2-methyl-4,5-dimethoxybenzylacrylonitrile (16 g.) and after18-20 hr. reflux gave2,4-diamino-5-(2'-methyl-4',5'-dimethoxybenzyl)pyrimidine. Wt.=11.5 g.(92%) m.p. 230°-231° C.

Example 71

The procedure of Example 64 was repeated usingβ-anilino-α-3,4-dimethoxy-5-bromobenzylacrylonitrile (62 g.) and gave2,4-diamino-5-(3',4'-dimethoxy-5'-bromo-benzyl)pyrimidine. Wt.=38 g.(70%) m.p. 203.5°-205° C.

Example 72

The procedure of Example 64 was repeated usingβ-anilino-α-p-benzyloxybenzylacrylonitrile (25 g.) and gave after 4 hr.reflux 2,4-diamino-5-(p-benzyloxybenzyl)pyrimidine. Wt.=20.5 g.. Thiswas converted to its acetate salt by treatment with acetic acid. Wt.=15g.

Example 73

2,4-Diamino-5-(p-benzyloxybenzyl)pyrimidine acetate (4.6 g.) in methanol(200 ml.) was hydrogenated at low pressure over 5% Palladium/Carbon. Thefiltrate after removal of catalyst was evaporated and the resultingresidue purified by dissolution in hot dilute acetic acid andre-precipitation with ammonium hydroxide to pH 9. Crystalline2,4-diamino-5-(p-hydroxybenzyl)pyrimidine was collected and washed withwater. Wt.=2.16 g. m.p. 300°-303° C.

Example 74

β-Morpholino-α-3,4,5-trimethoxybenzylacrylonitrile (32 g.), guanidinecarbonate (34 g.) and dimethylsulphoxide (50 ml.) were heated togetherat 160° C for 1 hr. with good stirring. The reaction mixture was cooledand poured into ice-water (200 ml) and gave2,4-diamino-5-(3',4',5'-trimethoxybenzyl)pyrimidine which was collectedand washed with water and acetone. Wt.=23.6 g (80%) m.p. 196°-198° C.

Example 75

The procedure of Example 74 was repeated usingβ-N-methylanilino-α-3,4,5-trimethoxybenzylacrylonitrile and gave2,4-diamino-5-(3',4',5'-trimethoxybenzyl)pyrimidine.

Example 76

The procedure of Example 74 was repeated usingβ-piperidino-α-3,4,5-trimethoxybenzylacrylonitrile and gave2,4-diamino-5-(3',4',5'-trimethoxybenzyl)pyrimidine.

Example 77

The procedure of Example 74 was repeated usingβ-pyrrolidino-α-3,4,5-trimethoxybenzylacrylonitrile and gave2,4-diamino-5-(3',4',5'-trimethoxybenzyl)pyrimidine.

Example 78

The procedure of Example 74 was repeated usingβ-dimethylamino-α-3,4,5-trimethoxybenzylacrylonitrile and gave2,4-diamino-5-(3',4',5'-trimethoxybenzyl)pyrimidine.

Example 79

The procedure of Example 74 was repeated usingβ-benzylamino-α-3,4,5-trimethoxybenzylacrylonitrile and gave2,4-diamino-5-(3',4',5'-trimethoxybenzyl)pyrimidine.

Example 80

The procedure of Example 74 was repeated usingβ-morpholino-α-3,4-dimethoxybenzylacrylonitrile and gave2,4-diamino-5-(3',4'-dimethoxybenzyl)pyrimidine.

Example 81

The procedure of Example 74 was repeated usingβ-dimethylamino-α-3,4-dimethoxybenzylacrylonitrile and gave2,4-diamino-5-(3',4'-dimethoxybenzyl)pyrimidine.

Exammple 82

The procedure of Example 74 was repeated usingβ-morpholino-α-piperonylacrylonitrile and gave2,4-diamino-5-piperonylpyrimidine.

Example 83

The procedure of Example 74 was repeated usingβ-morpholino-α-3,4,-dimethoxy-5-bromobenzylacrylonitrile and gave2,4-diamino-5-(3',4'-dimethoxy-5'-bromobenzyl) pyrimidine.

Example 84

The procedure of Example 64 was repeated usingβ-methoxy-α-3,4,5-trimethoxybenzylacrylonitrile (54 g.) and after 20 hr.reflux gave 2,4-diamino-5-(3',4',5'-trimethoxybenzyl)pyrimidine. Wt.=56g. (94%) m.p. 198°-200° C.

Example 85

Under the conditions of Ex. 24 theβ-hydroxy-β-(3,4-dichlorophenethylmethylsulfone, β-hydroxy-β(o, meta,p-iodophenyl)methylsulfones and β-hydroxy-β -(o-bromophenethylsulfones)were condensed with β-anilinopropionitrile to yield the correspondingβ-anilino-α-halogenobenzylacrylonitriles.

Example 86

The procedure of example 64 was repeated using the products of ex. 85 togive 2,4-diamino-5=(3',4'-dichlorobenzyl) pyrimidine, m.p. 237°-239°,2,4-diamino-5-(o-iodobenzyl) pyrimidine, m.p. 265°-267°,2,4-diamino-5-(m-iodobenzyl) pyrimidine, m.p. 220.5 -222°,2,4-diamino-5-(p-iodobenzyl) pyrimidine, m.p. 246°-248°, and2,4-diamino-5-(o-bromobenzyl) pyrimidine, m.p. 248°-250°.

Example 87

β-hydroxy-α-3,4,5-trimethoxy-benzylacrylonitrile 25 grams, denaturedethanol (70 ml.) 2,4-dimethyl aniline (14 ml.) refluxed together for 1hr. Solvent removed by evaporation and vacuumed and the residue waspoured into ice water. The resulting thick gum was collected andrecrystallized from methanol to give crystaline β-2,4-dimethylanidino-α-3,4,5-trimethoxybenzylacrylonitrile. Wt.=11g. (31% yield) M.P.123°-125° C.

Example 88

Procedure of Example 87 was repeated using 3,4,5-trimethoxyaniline andgave β-3,4,5-trimethoxybenzylacrylonitrile in 65% yield. M.P. 156°-161°C. Recrystallized from denatured ethanol.

Example 89

Procedure of Example 87 was repeated using 2,5-dichloroaniline and gaveβ-2,5,-dichloroanilino-α -3,4,5-trimethoxybenzylacrylonitrile. 20 g, 51%yield. A sample recrystallized from denatured ethanol melted at 130° C,resolidified, and then remelted at 150° C.

Example 90

Procedure of Example 87 was repeated using α-napthylamine 14.3gr. andgave crystaline β-1-napthylamino -α-3,4,5-trimethoxybenzylacrylonitrile.Wt.=26 gr. 70% yield, melting pt. 107°-109° C.

Example 91

The product from Example 87 was converted to trimethoprim by theprocedure of Example 64 in 4 hrs. Yield 92%.

Example 92

The product from Example 88 was converted to trimethoprim by theprocedure of Example 64 in 3 hrs. Yield above 90%.

Example 93

The product from Example 89 was converted to trimethoprim by theprocedure of Example 64 in 1.5 hrs. Yield 95%. This reaction wasrepeated as in Example 64 except at room temperature and useful yield oftrimethoprim was obtained in several hrs.

Example 94

The product from Example 90 was converted to trimethoprim by theprocedure of Example 64 in several hrs. Yield 72%.

Example 95

Methylα-(3,4,5-trimethoxyacetophenone) Sulphone ##STR11##

Charge into a 500 ml. three necked flask equipped with stirrer andreflux condenser, 27 gms. (0.69M) sodium amide, 225 ml.dimethylsulphoxide and 56.5 gm. dimethylsulphone (0.6M). Heat to 55° Cfor 1 hour with stirring, and cool to 50° C. Add 65.4 gm. (0.20M)3,4,5-trimethoxymethylbenzoate and heat to 60° C for 1 hour to completethe reaction.

Pour the mixture onto 1100 gm. of ice and acidify with 180 ml. diluteHCl (1:1). Cool in an ice bath and filter the crystalline product. Washwith 2×150 ml. of ice water and 2×100 ml. ice cold lower alcohol such asethanol. Air dry overnight or vacuum dry at 40° C to constant weight.The yield will be 74 gm. or 88% of theory of suitable intermediate forthe next step. A.N. Sample M.P. 147°-148° C Recrystallized from Ethanol

    ______________________________________                                                  Calculated Found                                                    ______________________________________                                        C           49.98        49.8                                                 H            5.59         5.54                                                ______________________________________                                    

Example 96

Reduction of methyl α(3,4,5-trimethoxyacetophenone) sulphone to thecorresponding alchohol ##STR12##

Set up a 3 neck 1 liter flask equipped with a stirrer in an ice bath.Charge with 38.1 gm. of methyl α(3,4,5-trimethoxyacetophenone) sulphone,100 ml. desalted water and 30 ml. ethanol and cool this slurry to +15°C. Add portion wise a precooled solution of 2 gm. sodium borohydride in40 ml. desalted water. The first few ml. will cause a slight foaming butit can be controlled easily with a few ml. of ethanol. Additionalethanol can be used to wash down the sides of the reaction flask.

At the end of the addition of the borohydride remove the cooling bathand stir for 1 hour. Completion of the reaction is checked by U.V. Coolthe slurry to +2° C and filter all solids. Wash with small amounts ofice water and dry in vacuum oven at 50° C to constant weight. The yieldwill be 34.2 gm. or 89.3% of theory. A.N. Sample M.P. 153°-154° CRecrystallized from ethanol

    ______________________________________                                                  Calculated Found                                                    ______________________________________                                        C           49.7         49.39                                                H            6.24         6.27                                                ______________________________________                                    

Example 97

ω-(Methylsulfinyl)3,4,5-Trimethoxyacetophenone ##STR13##

Into a three necked flask, equipped with condenser, stirrer andthermometer, charge 4.0 gm. sodium amide (hexane washed) and 75 ml.dimethyl sulphoxide (distilled and dried). Slowly warm (in an externalwater bath) to 45° C and the reaction begins. Raise temperaturegradually to 60° C and maintain for 1 hour, to complete.

Cool to +15° and add dropwise a solution of 12 gm.3,4,5-trimethoxymethylbenzoate in 25 ml. of dimethylsulphoxide. Keep thetemperature between 20°-25° C by external cooling. Stir 1/2 hour at roomtemperature and quench into 300 ml. ice water. Carefully acidify to pH5-6 with cold dilute hydrochloric acid.

Extract into chloroform 3×100 ml. wash the organic layer with 4×50 ml.water, dry over sodium sulphate, filter and flash evaporate all solvent.

The heavy oil will weigh 15 gm. and slowly crystallize on standing.

To purify; dissolve the thick oil in 75 ml. ethyl acetate, charcoal andcool the filtrate in an ice acetone bath. Filter and dry the whitesolid. Wt. = 10 gm.≈70% yield. M.P. 113°-115° C.

A.N. Sample M.P. 115°-116° C Recrystallized from acetone

    ______________________________________                                                  Calculated Found                                                    ______________________________________                                        C           53.05        52.69                                                H            5.92         5.84                                                ______________________________________                                    

Example 98

β-Hydroxy β-3,4,5-trimethoxyphenethylmethylsulphoxide ##STR14##

Combine 14 gm.ω(methylsulfinyl)3,4,5-trimethoxyacetophenone, 50 ml.desalted water and 35 ml. methanol. Cool to +15° C and with magneticstirring add slowly a solution of 0.5 gm. sodium borohydride in 10 ml.water. The reaction is exothermic but can be controlled between 15°-20°C with external cooling.

Stir at room temperature for 2 hours, check for completion by U.V. andfinally strip off methanol by vacuum at 45°-50° C.

Extract the aqueous solution with 3×75 ml. chloroform, wash with theorganic layer 1×75 ml. water, dry over magnessium sulphate, filter andevaporate to a clear thick oil. A few drops of ethyl acetate causescomplete crystallization. Weight = 14 gm. This is suitable for use inthe next step without further purification.

A.N. Sample P. 150°-155° C (Isomers) Recrystallized from Ethyl Acetate.

    ______________________________________                                                  Calculated Found                                                    ______________________________________                                        C           52.4         52.37                                                H            6.61         6.70                                                ______________________________________                                    

Example 99

α(3,4,5-Trimethoxybenzyl) β-anilinoacrylonitrile ##STR15##

Combine in a flask at room temperature 5.4 gm.β-hydroxy-β-3,4,5-trimethoxyphenethyl methyl sulphoxide, 3 gm.β-anilinopropionitrile, 25 ml. dimethylsulphoxide and 2.0 gm. sodiummethylate. Warm slowly with stirring, on a steam bath up to 90°-95° C.It gets very dark in color. Reaction, by U.V., is complete in 20 minutesat 95° C.

Quench in ice water and wash the dark oily precipitate by decantation.Dissolve in 15 ml. of ethanol and cool. Filter the heavy yellowcrystalline precipitate, wash with cold ethanol and hexane. Dry. Wt. = 2gm.≈ 31% yield. The U.V., I.R., and M.P. are identical to that preparedfrom the 3,4,5-trimethoxybenzaldehyde and β-anilinopropionitrile. Ph =phenyl.

Example 100

α(3,4,5-trimethoxybenzyl)-β-anilinoacrylonitrile ##STR16##

In a three neck flask equipped with stirrer, condenser and thermometer,charge 29 gm. β-hydroxy-β-3,4,5-trimethoxyphenethylmethylsulphone, 16.5gm. β-anilinopropionitrile and 40 ml. dimethylsulphoxide. Warm to 40° Cwith stirring, and gradually add 83 ml. of a 13.6% solution of potassiumtertiary butoxide in tertiary butanol. Maintain internal temperature at45° C for 1 hour and check for completion by U.V.

Strip as much alcohol as possible by vacuum using an external water bath(70° C) and quench in ice water (200 ml.). Stir until the thick oilturns crystalline an filter. Wash the cake with ice water and finallyhexane. Vacuum dry at 35° C to constant weight. The yield will be 32gm.* or theory of crudeα-(3,4,5-trimethoxybenzyl-β-anilinoacrylonitrile). The U.V. issatisfactory and it may be used directly in the preparation ofTrimethoprim.

Example 101

Trimethoprim 2,4-diamino-5-(3',4',5'-trimethoxybenzyl) pyrimidine

Prepare a guanidine solution from 15 gm. guanidine HCl, 10 gm. sodiummethylate, and 100 ml. ethanol. Cool, filter salt free, and combine with16 gm. α(3,4,5-trimethoxybenzyl)β-anilinoacrylonitrile. Reflux in asteam bath overnight, charcoal the hot solution with 2.0 gm. Darco G-60and evaporate to 1/4 volume. Cool to complete crystallization, filter,and wash with cold ethanol, acetone, and ether. Dry. Weight = 13+gm.˜91%theory. M.P. 198°-200° C.

Example 102

β-Hydroxy β-3,4,5-trimethoxyphenethylmethylsulphoxide

Sodium methylate (5.4 gm.) was dissolved in hot dimethylsulfoxide (50ml.), the solution was cooled to room temperature,3,4,5-trimethoxybenzaldehyde (18 gm.) was added, and the mixture wasstirred at room temperature for 2 hours. Water (100 ml.) was then addedto the mixture which was next extracted with chloroform. The chloroformextract was washed with water, dried over anhydrus sodium sulfate, andevaporated to dryness. The residual yellow oil crystallised on additionof ethylacetate. The crystals were collected and washed with pentane.Wt. = 14.8 gm. (59%) M.P. 160°-162° C (After recrystallisation fromethylacetate.) I.R. and U.V. spectra in agreement with structure.

    ______________________________________                                                  Calculated Found                                                    ______________________________________                                        C           52.4         52.37                                                H            6.61         6.70                                                ______________________________________                                    

What we claim is:
 1. The method of preparing a compound of the formula##STR17## which comprises reacting ##STR18## wherein R¹ -R⁴ are the sameor different and each is hydrogen, halogen, lower alkyl, lower alkoxy,or benzyloxy, or R³ and R⁴ taken together is methylenedioxy when both R¹and R² are hydrogen in the presence of a base selected from the groupconsisting of hydroxides, alkoxides and methylsulphinyl carbanion inassociation with an alkali metal or quaternary ammonium cation in apolar aprotic solvent compatible with and dissolving both reactants,wherein NR⁵ R⁶ is selected from the group consisting of anilino,N-methyl anilino, N-ethyl anilino where the phenyl ring thereof issubstituted by one or more halogen, alkyl or alkoxy, monoalkylamino,benzylamino, α-naphthylamino, β-naphthylamino, pyrrolidino, piperdino,piperazino and morpholino and wherein the said NR⁵ R⁶ group has not morethan 12 carbon atoms and can have only one hydrogen atom for R⁵ and R⁶.2. The method according to claim 1 in which the base ranges in amountfrom abount .3 to about 2 molar equivalents.
 3. The method according toclaim 2 in which the base is lower alkoxide anion.
 4. The methodaccording to claim 3 in which the alkoxide anion is methoxide.
 5. Themethod according to claim 1 in which R⁵ is hydrogen, R⁶ is phenyl, oneof R¹ -R⁴ is hydrogen and the others are methoxy at the 3,4 and 5positions of the ring.
 6. The method according to claim 1 in which thenitrile is β-morpholino-propionitrile.
 7. The method of claim 1 in whichthe nitrile is β-morpholino-propionitrile.
 8. The method of claim 1 inwhich the nitrile is β-anilinopropionitrile.
 9. The method of claim 1 inwhich the nitrile is β-piperidinopropionitrile.
 10. The method of claim1 in which the nitrile is β-pyrrolidinopropionitrile.